Double-packaged easily oxidizable article

Abstract: A packaged easily oxidizable article and a process for packaging the article are provided, wherein the deterioration of the easily oxidizable article by its oxidation during heat sterilization or storage is prevented. A hermetically sealed plastic vessel filled with an easily oxidizable article is double-packaged in a flexible packaging bag wherein a plastic layer having heat-sealing characteristics, an inorganic oxide layer and a plastic layer are laminated in order from the inside.

Description: Field of the Invention The present invention relates to a double-packaged easily oxidizable article, comprising a hermetically sealed plastic vessel filled with an easily oxidizable article such as easily oxidizable medical and pharmaceutical products, medical equipment, cosmetic products, foods and drugs, which require heating and/or sterilization, which is packaged with a packaging material having high oxygen barrier properties as well as resistance to heat sterilization, and to the packaging process thereof. Description of the Related Art Recently, many easily oxidizable articles which require heating and/or sterilizing treatment have been packed in plastic vessels, and made available after being subjected to heat sterilization treatment. However, due to insufficient oxygen barrier properties of the vessel, problems have been caused in that the easily oxidizable article has been deteriorated by the oxygen permeating into the vessel during the heat sterilization or storage. For example, a material such as an amino acid transfusion containing tryptophan causes the problem of browning or generation of a foreign odor and the like by the oxidation. Accordingly, when a vessel filled with a medical and pharmaceutical liquid drug, which is susceptible to oxidation, for example, is to be sterilized by heating, as described in Japanese Patent Laid Open Hei 57-206447, a method has been employed wherein a retort is pressurized with an inert gas to carry out high pressure sterilization in a saturated steam atmosphere practically free from oxygen so that the content is not oxidized nor degenerated during the heat sterilization. The conventional heat sterilization treatment method, however, has been disadvantageous from the view point of requiring a special apparatus, a complicated procedure and a high cost. After carrying out such sterilization by heat, in order to prevent the oxidation and deterioration of the content during the storing period until it is actually used, the vessel filled with the easily oxidizable medical and pharmaceutical liquid drug and the like is covered and hermetically sealed in a bag made of a laminated film comprising an intermediate layer that has high oxygen barrier properties, such as polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyvinylidene chloride, aluminiuum foil or aluminium deposited layer and the like (Japanese Patent Laid-Open Sho 59-80256, Japanese Patent Laid-Open Hei 02-180129). In addition thereto according to Japanese Patent Publication No. Hei 03-1021, a vessel filled with an easily oxidizable liquid drug is packaged in a sheathing bag made of a laminate having polyvinylidene chloride as an oxygen barrier layer, and sterilized by heating under that condition. It is well known, however, that the oxygen barrier properties of polyvinyl alcohol or ethylene-vinyl alcohol copolymer are very much decreased under high humidity condition, and the oxygen barrier properties of polyvinylidene chloride are lowered very much under high temperature condition. For these reasons when the vessel is previously packaged in the flexible packaging bag containing these materials, and heat sterilization is carried out in a retort without replacing the atmosphere with an inert gas, it is very difficult to control the oxidation deterioration of the content during the heat sterilization. In addition to that, the material using the polyvinyl alcohol or ethylene-vinyl alcohol copolymer retains the extremely lowered oxygen barrier properties even after the heat sterilization treatment, thus the capability of controlling the oxidation deterioration of the liquid drug during storage is very much lowered as well. Since the product using the polyvinylidene chloride also has lowered oxygen barrier properties by the heat sterilization treatment to a considerable level as it is shown in Japanese Patent Publication No. Hei 03-1021, though not so much as that of the polyvinyl alcohol or ethylene-vinyl alcohol copolymer, it is not favorable to carry out the heat sterilization treatment of the vessel while it is packaged in such a sheathing bag, and to store it in such a bag, from the view point of preventing the easily oxidizable article from being oxidized and deteriorated. On the other hand, when a metal foil such as aluminium foil, or a film wherein a metal such as aluminium is deposited is used for the flexible packaging bag to carry out the sterilization by heat, the inside of the vessel cannot be seen and it disturbs the visual inspection of the content for finding out foreign matter after the heat sterilization treatment. The heat sterilization treatment tends to generate pin holes etc. which lower the oxygen barrier properties. For the above reasons, the packing of the vessel in a flexible packaging bag having such an oxygen barrier material must practically be carried out after the heat sterilization treatment. Accordingly, the process to package the vessel in the flexible packaging bag generally comprises the steps of letting the vessel cool after the heat treatment, wiping off the water on the surface, and packaging it in an inert gas atmosphere. This process is disadvantageous since it is complicated, time-consuming and requires a special apparatus. It is also known that a flexible plastic bag in which a film having high oxygen barrier properties such as polyvinylidene chloride is laminated, is directly filled with a medical and pharmaceutical liquid drug, and then subjected to heat sterilization treatment (Japanese Patent Laid-Open Sho 63-164950, Japanese Patent Laid-Open Hei 02-204033). As mentioned before, however, the product utilizing polyvinylidene chloride has such a defect as lowering the oxygen barrier properties during the heat sterilization as well as after the heat sterilization. Also there is a defect of lowering safety since when the plastic bag is contacted directly with the medical and pharmaceutical liquid drug, its ingredients migrate into the medical and pharmaceutical liquid drug. There is another known process (Japanese Patent Laid-Open Sho 60-236651) wherein a silicone layer having oxygen barrier properties is formed on an external surface or an internal surface of a vessel, then the vessel is filled with a liquid drug and heat sterilization treatment is carried out under pressure after replacing the atmosphere of the autoclave with an inactive gas. However, the oxygen permeability of the vessel is high and it is insufficient to prevent the oxidation of the easily oxidizable article. There was also another defect that the silicone layer which is existing on the surface of the vessel under unprotected condition tends to be damaged, and that increases the oxygen permeability. For the heat sterilization, the atmosphere of the autoclave must be replaced with an inactive gas and the autoclave must be pressurized, thus the procedure is complicated and requires a special apparatus. There is still another known process (Japanese Patent Laid-Open Sho 62-103139, Japanese Patent Laid-Open Sho 63-186652, Japanese Patent Laid-Open Hei 03-244535) wherein a plastic bag or pouch having oxygen barrier properties in which silicon oxide layer or aluminium oxide layer is laminated, is directly filled with a medical and pharmaceutical liquid drug or food and subjected to heat sterilization treatment. In such a case, however, when the plastic bag or pouch is directly contacted with the medical and pharmaceutical liquid drug or food, the components of the plastic bag or pouch also migrate into the medical and pharmaceutical liquid drug or food to lower the safety, or to cause a foreign taste or foreign odor. Since a material having a silicon oxide layer or aluminum oxide layer cannot be processed by blow molding, when a plastic bag for a transfusion is to be produced, for example, a stick-shape liquid drug injection nozzle must be attached later, and the attaching step tends to produce pin holes in the silicon oxide layer or aluminum oxide layer which results in lowering the oxygen barrier properties. Problem to be Solved by the Invention The problem to be solved by the invention is to provide a packaged easily oxidizable article; comprising a hermetically sealed vessel filled with the easily oxidizable article, which allows sterilization by heat under oxygen barrier condition, prevents the components of the vessel from migrating to the easily oxidizable article, and has high inhibitory power on the oxidation deterioration of the easily oxidizable article during storage since the oxygen barrier properties are maintained at a high level even after the heat sterilization, and to provide a process of packaging the easily oxidizable article. Means for Solving the Problem As a result of extensive research in order to solve the above-mentioned problem, the present invention is achieved by filling a vessel which has heat resistance, scarcely allows its components to migrate to its contents, and which can firmly prevent components outside from permeating into it, with an easily oxidizable article and by packaging the vessel in a flexible packaging bag which has high heat resistance and high oxygen barrier properties, keeps the oxygen barrier properties at a high level even under high humidity and high temperature condition such as sterilization by heat, and which does not loose the high oxygen barrier properties even after the heat sterilization. That is to say, the present invention provides a double-packaged easily oxidizable article, comprising a flexible packaging bag in which one or more plastic vessels filled with an easily oxidizable article, are packaged and hermetically sealed; wherein the flexible packaging bag is flexible and comprises a plastic layer having heat-sealing characteristics, an inorganic oxide layer and a plastic layer laminated in an ascending order from the inside to the outside of the bag. This invention also provides a double-packaged easily oxidizable article which is obtained by subjecting the double-packaged easily oxidizable article to heat sterilization, and a packaging process of the double-packaged easily oxidizable article. Effects Easily oxidizable articles to be used in the present invention are not specifically limited as far as they contain an oxidizable component and require heating and/or sterilization. For example, they include medical and pharmaceutical liquid drugs such as amino acid preparations, fat emulsion preparations, vitamin preparations, nucleic acid preparations, enteral feeding nutrient preparations, tube feeding nutrient preparations, and ophthalmic solutions. The representative example includes amino acid transfusion solutions, Medical equipment includes a tube to be introduced into a body cavity or an instrument for blood transfusion which is made of a material susceptible to oxidation. Cosmetic products include milky lotions, lotions and creams containing proteins such as collagen and chitin, amino acids, amino acid derivatives, unsaturated fatty acids and vitamins. Foods include, for example, margarine, mayonnaise and beverages and the like which are enriched with vitamin E or unsaturated fatty acids. In addition to those, drugs and foods which require heat reaction are also included as examples. The vessel to be filled with the easily oxidizable article is desired to be a vessel of a transparent plastic which allows observation of the contents by eyes. The hardness of the vessel depends on the use. Soft bags are for transfusion, for example, and hard vessels are for ophthalmic solutions and the like. As the material, any material can be used as far as it has such heat resistance that it can resist to sterilization by heat, as far as it allows little migration of components from the vessel to the easily oxidizable article filled in the vessel, and as far as it can firmly prevent any component except for a gas from migrating from outside to the easily oxidizable article through the vessel. Such a material includes, for example, a single layer or a laminate of layers a polyolefin material such as polyethylene, polypropylene, polybutene or their copolymers, as well as of vinyl chloride, cross-linked ethylene-vinyl acetate copolymer resin, polyester, polycarbonate, polyacrylate, polyamide, and fluorine resin and the like. The vessel is made by molding by heat sealing, blow molding, orientation-blow molding and the like. The flexible packaging bag is made of a laminate comprising a plastic layer having heat-sealing characteristics, an inorganic oxide layer and a plastic layer laminated in an ascending order from the inside of the bag. The flexible packaging bag has transparency which allows visual recognition of the contents and has resistance to sterilization by heat. The oxygen permeability of the flexible packaging bag before and after the heat sterilization treatment is not more than 4.0 ml/m 2 24 hours measured under the condition of 25 °C, relative humidity of 100 % and 1 atmospheric pressure (in conformity with ASTM D 3985), preferably not more than 2.0 ml/m 2 24 hours, and most preferably not more than 1.0 ml/m 2 24 hours. Fig.1 is an illustrative example of a sectional view of such a laminate, but the present invention is not limited to it. Referring to Fig.1, reference number 1 refers to a plastic layer having heat-sealing characteristics, which comprises a single layer or two or more layers of a polyolefin such as polyethylene, polypropylene, polybutylene or their copolymers, as well as vinyl chloride, ethylene-vinyl acetate copolymer. Reference number 2 refers to an inorganic oxide layer which is formed on a plastic layer 3 made of a polyester film such as biaxially oriented polyethylene terephthalate or polycarbonate, as well as a polyamide film, a polyolefin film, and a polyacrylonitrile film. As an inorganic oxide layer, any film as far as it has high transparency in visible light range and high oxygen barrier properties is suitable and examples include a silicon oxide layer, aluminium oxide layer, titanium oxide layer, tin oxide layer and indium oxide layer. The silicon oxide layer and aluminium oxide layer are particularly preferable. The inorganic oxide layer can be formed on both surfaces of the plastic layer 3. A plurality of plastic layers and a plurality of inorganic oxide layers can be laminated in order to improve the oxygen barrier properties. In such a case, the inorganic oxide layer does not have to be the same kind. For forming an inorganic oxide layer, for example, silicon oxide layer, pre-treatment of the surface of the plastic layer 3 is not particularly needed, however, in some cases, the surface can be activated by chemical processing such as hydrolysis or discharging treatment and the like, or the surface can be treated with a chemical agent having an active residual group such as a silane coupling agent and the like. The silicon oxide layer can be formed by depositing or sputtering silicon or silicon oxides such as silicon monoxide or silicon dioxide in vacuum or in an inert gas, or by reactive deposition or reactive sputtering of silicon and/or silicon oxides excluding the use of silicon dioxide alone. When a silicon oxide layer is formed, a small amount of an inorganic oxide can be mixed with the silicon or silicon oxide. Silicon oxide layers produced from the mixture of silicon monoxide and silicon dioxide particularly provide good gas barrier properties. From the view point of the gas barrier properties and flexibility, the thickness of the silicon dioxide is preferably 5 to 600 nm (50 - 6000 Å) and a particularly preferable thickness is 10 to 150 nm (100 - 1500 Å). (The details of its formation are described, for example, in Japanese Patent Laid-Open Hei 01-252768, Japanese Patent Laid-Open Hei 02-34328, Japanese Patent Laid-Open Hei 02-122924, Japanese Patent Laid-open Hei 03-23333, Japanese Patent Laid-Open Hei 02-221366, Japanese Patent Laid-Open Hei 04-99263, Japanese Patent Laid-Open Hei 04-115940, Japanese Patent Laid-Open Hei 04-165064, Japanese Patent Laid-Open Hei 04-337067, Japanese Patent Laid-Open Hei 04-366142, Japanese Patent Laid-Open Hei 04-251736, and Japanese Patent Laid-Open Hei 04-341560). Formation of the aluminium oxide layer does not particularly require pre-treatment of the surface of the plastic layer 3, however, in some cases the surface of the plastic layer can be activated by chemical treatment such as hydrolysis or discharging treatment and the like, or can be treated with a chemical having an active residue such as a silane coupling agent and the like. The aluminium oxide layer can be formed by deposition or sputtering of an aluminium oxide such as AlO, Al 2 O 2 , and Al 2 O 3 in vacuum or in an inactive gas, or by so-called reactive deposition or reactive sputtering wherein aluminium is melted and evaporated and an aluminium oxide layer is formed on a substrate while oxygen gas is introduced into the vacuum vessel. When the aluminium oxide layer is formed, an impurity such as a metal including aluminium, copper, iron, tungsten, molybdenum, silicon, as well as zirconium oxide, magnesium oxide, tungsten oxide, molybdenum oxide, boron nitride and silicon oxide in an amount of not more than about 10 % by weight can be contained. The aluminium oxide layer to be formed can be either crystalline or non-crystalline, however, non-crystalline aluminium oxide is more preferable since it has resistance to bending. From the view point of the gas barrier properties and flexibility, the thickness of the aluminium oxide layer is preferably 3 to 50 nm (30 - 500 Å), and a particularly preferable thickness is 10 - 200 nm (100 - 2000 Å ). Details of its formation are described in, for example, Japanese Patent Laid-Open Sho 62-101428, Japanese Patent Laid-Open Sho 62-179935, Japanese Patent Laid-Open Sho 62-220330, Japanese Patent Laid-Open Sho 63-222849, Japanese Patent Laid-Open Sho 63-223163, Japanese Patent Laid-Open Hei 03-244535, Japanese Patent Laid-Open Hei 03-23933, Japanese Patent Laid-Open Hei 03-108531, and Japanese Patent Laid-Open Hei 04-257437.) The plastic layer 1 having heat-sealing characteristics and an inorganic oxide layer 2 are coated with an adhesive layer 4 as shown in Fig. 1. As the adhesive layer 4, a material which has good adhesive force to the plastic layer 1 having the heat-sealing characteristics as well as to the inorganic oxide layer 2, and which scarcely lowers the gas barrier properties, is used. Examples of such a material include a modified polyolefin adhesive agent, a polyurethane type adhesive agent, a modified polyester type adhesive agent, an epoxy resin type adhesive agent, a photo-setting resin type adhesive agent and a silicone type adhesive agent. A plastic layer 5 made of a material which is the same as or different from that of the plastic layer 3 can be further laminated on the external surface of the plastic layer 3 in order to improve the bag breaking strength, stab strength, gas barrier properties, and resistance to heat sterilization of the flexible packaging bag as a whole. As a material for the plastic layer 5, polyolefin, polyester, polyamide, polyacrylonitrile, polycarbonate, liquid crystalline polymer, silicone and a fluorine resin and the like are desirable. Such lamination can also be provided between the plastic layer 1 having heat-sealing characteristics and the inorganic oxide layer 2. A plastic layer can be further laminated on the external surface, if necessary. The plastic layer 3 and the plastic layer 5 may be adhered with an adhesive layer 6. An example of such adhesive agent includes a modified polyolefin adhesive agent, a polyurethane type adhesive agent, a modified polyester type adhesive agent, an epoxy resin type adhesive agent, a photo-setting resin type adhesive agent and a silicone type adhesive agent. Another material having oxygen barrier properties such as a polyvinyl alcohol layer, an ethylene-vinyl alcohol copolymer layer or a polyvinylidene chloride layer can be laminated between the plastic layer 1 having heat-sealing characteristics and the inorganic oxide layer 2, in order to further reduce the gas permeability. In such a case, since the inorganic oxide layer has steam barrier properties, the lowering of the oxygen barrier properties of the polyvinyl alcohol layer or the ethylene-vinyl alcohol copolymer layer after the heat sterilization can be avoided. The flexible packaging bag is formed into a bag shape by heat-sealing of the peripheries of a pair of thus produced laminated bodies. According to a packaging process for providing the double-packaged easily oxidizable article of the present invention, a vessel which is to be filled with the easily oxidizable article is firstly molded, and filled with the article then hermetically sealed. When the vessel to be filled with the easily oxidizable article is a transfusion solution bag, the molding of the vessel can be done by blow molding process, or orientation blow molding process, or by attaching a liquid drug injection nozzle at the same time or immediately after the heat-sealing of the peripheries. One or more vessels thus filled and sealed are packaged in a flexible packaging bag formed by such a process as sealing three sides. For packaging the vessels, a sheathing material which is already made into a bag can be used, or the vessel is held between a pair of laminated films then the peripheries of the laminated films are heat-sealed to make a flexible packaging bag containing the vessel therein. Then either vacuum packaging, wherein the air is released from the opening of the flexible packaging bag, and the opening is heat-sealed or packaging with inactive gas flush wherein an inert (inactive) gas is blown into the bag from the opening to replace the inside atmosphere with the inactive gas, and then the opening is heat-sealed, is carried out. The double-packaged easily oxidizable article thus produced, is shown in Fig.2. Immediately after the vessel is packaged in the flexible packaging bag, heat sterilization treatment is carried out. The heat sterilization treatment is carried out by so-called retort sterilization wherein the package is kept in high pressure steam atmosphere or hot water for a predetermined length of time. The retort sterilization is carried out in a normal retort and the pressure control is not required to be done with an inactive gas and the like. The temperature and the time for retort sterilization are not particularly limited, but the condition is preferable such that the easily oxidizable article is sterilized or heat reaction is completed but it is not deteriorated. The sterilization treatment is normally carried out at 115°C for 30 minutes, or at 121°C for 20 minutes. In such a case, the pressure of the retort is made higher than the vapor pressure of the easily oxidizable article at the temperature of the sterilization by about 9,8 - 196 kPa (0.1 - 2.0 kg/cm 2 ), and the pressurization is controlled by blowing pressurized air. Since the flexible packaging bag comprises an inorganic oxide layer having high gas barrier properties, the oxygen in the pressurized air can be prevented from entering and thus the oxidation and deterioration of the substance in the retort can be prevented. After all of the above steps, the visual inspection of the content is carried out. Since both the vessel to be filled with the easily oxidizable article and the flexible packaging bag have transparency, the presence of a foreign matter can be easily recognized from outside. Accordingly, the quality control can be easily done to secure high safety. After that, the product is supplied to hospitals and the like as it is or after being packed in a box. The above-mentioned series of steps of a packaging process for a double packaged easily oxidizable article, is desired to be carried out continuously in order to prevent the degeneration or putrefaction of the contents by contacting the vessel filled with the easily oxidizable article with air. As the material used for the vessel filled with the easily oxidizable article scarcely allows its components to migrate to the easily oxidizable article during the heat sterilization or storage, and prevents outside substances except for a gas from permeating, the migration of components from the flexible packaging bag into the easily oxidizable article can be greatly inhibited to secure high safety. An oxygen adsorber, a deodorizing agent, a carbon dioxide adsorber, a drying agent, a hydrogen sulphide adsorber, a fragrance and the like can be provided between the vessel and the flexible packaging bag of the present invention, if necessary, for such a purpose as to avoid the deterioration of the contents, expansion prior to the opening of the seal, and to avoid bad smell at the time of opening the seal. The flexible packaging bag having the inorganic oxide layer which is used in the present invention has high gas barrier properties also to other gases in addition to oxygen, and it can be applied for such uses that require gas barrier properties. For example, as it has also steam barrier properties, the entering of water from outside or diffusion of water to outside can be prevented. Accordingly, it can be applied for packaging a powder or a solid substance such as an amino acid or a nucleic acid which are deliquescent or which might absorb humidity to be concreted or for packaging a substance which might be denatured by drying or a solution wherein the concentrations of the components might be changed by drying. It can also be applied for packaging a substance which is desired not to be exposed to carbon dioxide. It is also useful for such a purpose as to prevent leaking of the smell of the contents. Examples Some examples of the present invention will be shown as follows, but the present invention is not limited to those examples. In those examples, "GT 1000R" (Trade Name) produced by Toyo Ink Mfg. Co., Ltd. was used as a silicon oxide layer/biaxially oriented polyethylene terephthalate film (thickness 12 µm), and "VM-PET1011HG" (Trade Name) produced by Toyo Metallizing Co., Ltd. was used as an aluminium oxide layer/biaxially oriented polyethylene terephthalate film (thickness 12 µm). As resin films having relatively high oxygen barrier properties used in reference examples, "SARAN UB (Trade Name) produced by Asahi Chemical Industry Co., Ltd. which is a vinylidene chloride copolymer resin (PVDC) biaxially oriented film (thickness 15 µm), "EVAL film EF-RT" (Trade Name) produced by Kuraray Co., Ltd. which is an ethylene-vinyl alcohol copolymer resin (EVOH) film (thickness 15 µm), and "OSM film" (Trade Name) produced by Toyobo Co., Ltd. which is a polymethaxylylene adipamide resin (MXD6) biaxially oriented film (thickness 15 µm) were used. The oxygen permeability of the film was measured by using "Oxtran Model 100" which is an oxygen permeability measuring apparatus produced by MODERN CONTROLS, INC. under the conditions of 25 °C, relative humidity of 100 % and 1 atm (in conformity with ASTM D 3985). The degree of yellowing of a tryptophan aqueous solution due to its oxidation deterioration was obtained by measuring its transmissivity (T %) at a wave length of 430 nm by using "U-3210" which is a recording spectrophotometer produced by Hitachi Ltd. The degree of elution of the components of a bag material into an aqueous solution packed in the bag was obtained by measuring the absorbancy of the solution by the above-mentioned recording spectrophotometer at the wave lengths of 210 nm, 220 nm and 240 nm. Example 1 Two opposed non-oriented polypropylene films (thickness of 110 µm) were cut to a size of 150 mm x 190 mm, three sides were sealed in a width of 5 mm, and 200 ml of a tryptophan solution having an L-tryptophan concentration of 0.4 g/dl and pH of 6.6, which was prepared from deoxygenated water, was filled through the opening, immediately after the preparation of the solution, then the atmosphere was replaced with nitrogen gas, and the opening was heat-sealed hermetically. This vessel was immediately put in a flexible packaging bag which was produced by sealing 3 sides of two laminated films of 180 mm x 210 mm, in a width of 5 mm, the film having a structure of non-oriented polypropylene (thickness of 70 µm)/polyurethane adhesive agent (5 g/m 2 )/silicon oxide layer/biaxially oriented polyethylene terephthalate (thickness of 12 µm), keeping the non-oriented polypropylene side inside. The bag was then set in a vacuum packaging vessel of an automatic vacuum gas packaging machine, model "FVS-420-G" produced by Furukawa Seisakusho Co., Ltd. in such a way that the opening of the flexible packaging bag could be heat-sealed, then the pressure inside of the vacuum packaging vessel was reduced by an oil hydraulic vacuum pump, to evacuate the air between the inner bag and the flexible packaging bag, and the opening of the flexible packaging bag was heat-sealed when the degree of vacuum inside of the vessel reached about 267 Pa (2 Torr). The package thus vacuum packed was placed in a retort apparatus and heat sterilization treatment was carried out in pressurized hot water at 121°C for 30 minutes, then it was stored under a condition of 44°C and relative humidity of 80 %. The oxygen permeability of the flexible packaging bag before and after the heat sterilization was measured and the change was examined. The yellowing degree of the contents after the heat sterilization as well as during the storing test at 44°C and under relative humidity of 80 % was measured with time. Example 2 Example 2 was carried out in a manner analogous to that of Example 1, but by replacing the pressurized hot water with high pressure steam in order to carry out the heat sterilization treatment at 121°C for 30 minutes. Example 3 Example 3 was carried out in a manner analogous to that of Example 1, but by replacing vacuum packaging with nitrogen gas flush packaging, in which a nitrogen gas flush nozzle was plugged into an opening of the flexible packaging bag, and the bag was set in a vacuum packaging vessel of an automatic vacuum gas packaging machine, model "FVS-420-G" produced by Furukawa Seisakusho Co., Ltd. in such a way that the opening of the flexible packaging bag could be heat-sealed after charging the gas. Then the pressure inside of the vacuum packaging vessel was reduced by an oil hydraulic vacuum pump, to evacuate the air between the inner bag and the flexible packaging bag, and nitrogen gas was blown through the nozzle into the space between the inner bag and the flexible packaging bag when the degree of vacuum inside the vessel reached about 267 Pa (2 Torr), till the amount of the nitrogen gas charged became about 10 ml, and the opening of the flexible packaging bag was heat-sealed immediately. Example 4 Example 4 was carried out in a manner analogous to that of Example 1, except that a laminated material wherein non-oriented polypropylene (thickness 70 µm), polyurethane adhesive agent (5 g/m 2 ), silicon oxide layer, biaxially drawn polyethylene terephthalate (thickness 12 µm), polyurethane adhesive agent (5 g/m 2 ) and biaxially drawn polyethylene terephthalate (thickness 12 µm) were laminated in this order from the inside, was used for the flexible packaging bag. Example 5 Example 5 was carried out in a manner analogous to that of Example 2, except that a laminated material wherein non-oriented polypropylene (thickness 70 µm), polyurethane adhesive agent (5 g/m 2 ), silicon oxide layers biaxially drawn polyethylene terephthalate (thickness 12 µm), polyurethane adhesive agent (5 g/m 2 ) and biaxially drawn polyethylene terephthalate (thickness 12 µm) were laminated in this order from inside was used for the flexible packaging bag. Example 6 Example 6 was carried out in a manner analogous to that of Example 1, except that a laminated material wherein non-oriented polypropylene (thickness 60 µm), polyurethane adhesive agent (5 g/m 2 ), aluminium oxide layer, biaxially oriented polyethylene terephthalate (thickness 12 µm), polyurethane adhesive agent (5 g/m 2 ), aluminium oxide layer and biaxially oriented polyethylene terephthalate (thickness 12 µm) were laminated in this order from the inside, was used for the flexible pakacking bag. Example 7 Example 7 was carried out in a manner analogous to that of Example 1, but by replacing the tryptophan solution with twice distilled water, and by carrying out heat sterilization at 121°C for 20 minutes. After the heat sterilization, the degree of elution of the components of the bag material into the packed distilled water was measured. Example 8 Example 8 was carried out in a manner analogous to that of Example 2, but by replacing the tryptophan solution with twice distilled water, and by carrying out heat sterilization at 121°C for 20 minutes. After the heat sterilization, the degree of elution of the components of the bag material into the packed distilled water was measured. Example 9 Example 9 was carried out in a manner analogous to that of Example 3, but by replacing the tryptophan solution with twice distilled water, and by carrying out heat sterilization at 121°C for 20 minutes. After the heat sterilization, the degree of elution of the components of the bag material into the packed distilled water was measured. Example 10 Example 10 was carried out in a manner analogous to that of Example 1, but by replacing the tryptophan solution with twice distilled water, and by carrying out heat sterilization at 121°C for 20 minutes. After the heat sterilization, the degree of elution of the, components of the bag material into the packed distilled water was measured. Example 11 Example 11 was carried out in a manner analogous to that of Example 6, but by replacing the tryptophan solution with twice distilled water, and by carrying out heat sterilization at 121°C for 20 minutes. After the heat sterilization, the degree of elution of the components of the bag material eluted into the packed distilled water was measured. Reference example 1 Two opposed non-oriented polypropylene films (thickness of 110 µm) were cut to a size of 150 mm x 190 mm, three sides were sealed in a width of 5 mm, and 200 ml of a tryptophan solution having the L-tryptophan concentration of 0.4 g/dl and pH of 6.6, which was prepared from deoxygenated water, was filled through the opening, immediately after the preparation of the solution, then the atmosphere was replaced with nitrogen gas, and the opening was heat-sealed hermetically. This was placed in a retort apparatus without delay, and heat sterilization treatment was carried out in pressurized hot water at 121°C for 30 minutes. Then it was stored under a condition of 44°C and relative humidity of 80 %. The oxygen permeability of the bag before and after the heat sterilization was measured and the change was examined. The yellowing degree of the contents after the heat sterilization as well as during the storing test at 44°C and under relative humidity of 80 % was measured with the time. Reference Example 2 Reference Example 2 was carried out in a manner analogous to that of Reference Example 1, but by replacing the pressurized hot water with high pressure steam in order to carry out the heat sterilization treatment at 121°C for 30 minutes. Reference Example 3 Reference Example 3 was carried out in a manner analogous to that of Reference Example 1, except that a laminated material wherein a laminated material wherein non-oriented polypropylene (thickness 65 µm), polyurethane adhesive agent (5 g/m 2 ), biaxially oriented PVDC (thickness of 15 µm), polyurethane adhesive agent (5 g/m 2 ) and non-oriented polypropylene (thickness 50 µm) were laminated in this order from the inside, was used for the flexible packaging bag. Reference Example 4 Reference Example 4 was carried out in a manner analogous to that of Reference Example 2, except that a laminated material wherein non-oriented polypropylene (thickness 65 µm), polyurethane adhesive agent (5 g/m 2 ), biaxially oriented PVDC (thickness of 15 µm), polyurethane adhesive agent (5 g/m 2 ) and non-oriented polypropylene (thickness 50 µm) were laminated in this order from the inside, was used for the flexible packaging bag. Reference Example 5 Reference Example 5 was carried out in a manner analogous to that of Reference Example 1, except that a laminated material wherein non-oriented polypropylene (thickness 70 µm), polyurethane adhesive agent (5 g/m 2 ), EVOH (15 µm), polyurethane adhesive agent (5 g/m 2 ), biaxially oriented polyethylene terephthalate (thickness 12 µm) were laminated in this order from the inside, was used for the flexible packaging bag. Reference Example 6 Reference Example 6 was carried out in a manner analogous to that of Reference Example 1, except that a laminated material wherein non-oriented polypropylene (thickness 70 µm), polyurethane adhesive agent (5 g/m 2 ), biaxially oriented MXD6 (15 µm), polyurethane adhesive agent (5 g/m 2 ), biaxially oriented polyethylene terephthalate (thickness 12 µm) were laminated in this order from the inside, was used for the flexible packaging bag. Reference Example 7 Reference Example 7 was carried out in a manner analogous to that of Reference Example 1, but by replacing the tryptophan solution with twice distilled water, and by carrying out heat sterilization at 121°C for 20 minutes. After the heat sterilization, the degree of elution of the components of the bag material into the packed distilled water was measured. Reference Example 8 Reference Example 8 was carried out in a manner analogous to that of Reference Example 2, but by replacing the tryptophan solution with twice distilled water, and by carrying out heat sterilization at 121°C for 20 minutes. After the heat sterilization, the degree of elution of the components of the bag material into the packed distilled water was measured. Reference Example 9 Two laminated films of 150 mm x 190 mm, each having a structure of non-oriented polypropylene (thickness 70 µm)/polyurethane adhesive agent (5 g/m 2 )/silicon oxide layer/biaxially oriented polyethylene terephthalate (thickness 12 µm), were opposed by keeping the non-oriented polypropylene side inside, and three sides were sealed in a width of 5 mm, and twice distilled water was packed through the opening, then the opening was heat-sealed hermetically. It was immediately placed in a retort apparatus and heat sterilization treatment was carried out in pressurized hot water at 121°C for 20 minutes. After the heat sterilization, the degree of elution of the components of the bag material into the packed distilled water was measured. Reference Example 10 Reference Example 10 was carried out in a manner analogous to that of Reference Example 9, but by replacing the pressurized hot water with high pressure steam in order to carry out the heat sterilization treatment at 121°C for 20 minutes. Reference Example 11 Two laminated films of 150 mm x 190 mm, each having a structure of non-oriented polypropylene (thickness 60 µm)/polyurethane adhesive agent (5 g/m 2 )/aluminium oxide layer/biaxially oriented polyethylene terephthalate (thickness 12 µm)/polyurethane adhesive agent (5 g/m 2 )/aluminium oxide layer/biaxially oriented polyethylene terephthalate (thickness 12 µm), were opposed by keeping the non-oriented polypropylene side inside, and three sides were sealed in a width of 5 mm, and twice distilled water was packed through the opening, then the opening was heat-sealed hermetically. It was immediately placed in a retort apparatus and heat sterilization treatment was carried out in pressurized hot water at 121°C for 20 minutes. After the heat sterilization, the degree of elution of the components of the bag material into the packed distilled water was measured. The changes in the oxygen permeability before and after the heat sterilization are shown in Table 1. The change in the nature of the tryptophan solution with the time, before and after the heat sterilization as well as during the storing test are shown in Table 2. The results show that the flexible packaging bag having the inorganic oxide layer has higher oxygen barrier properties than others, causes less changes in its oxygen permeability before and after the heat sterilization, and has high inhibitory power on the oxidation and the deterioration of the tryptophan solution, which is the content of the bag, during the heat sterilization as well as during the storing test. Also, the degrees of elution of the components of the bag material into the packed liquid drug after the heat sterilization are compared and shown in Table 3. This table shows that elution of the components of the bag material into the packed liquid drug, as impurities, can be largely prevented by the use of a bag material having an inorganic oxide layer for a flexible packaging bag, and by the use of an inner bag made of a material which scarcely contains such components that are easily eluted into the liquid drug, and which has relatively high barrier properties to such a component that is contained within the flexible packaging bag and that is easily eluted into the liquid drug, rather than by directly filling the bag material having the inorganic oxide layer, with the liquid drug. As described above, the flexible packaging bag of the double-packaged easily oxidizable article of the present invention is found to have high oxygen barrier properties, allows the heat sterilization of the contents packaged in the flexible packaging bag, since it shows almost no change in the oxygen barrier properties before and after the heat sterilization treatment, and has high inhibitory power on oxidation and deterioration of the easily oxidizable article during the heat sterilization and the storing period. By providing a vessel filled with the easily oxidizable article in the flexible packaging bag, the migration of the components of the bag material into the contents can be almost completely eliminated, thus the migration of the components of the bag material into the contents, that occurs when the easily oxidizable article is directly packed in a bag of high oxygen barrier capacity, and then subjected to sterilization by heat, can be substantially prevented. In addition to that, the double packaged easily oxidizable article can be made to have transparency, the mixing of a foreign substance to the content can be easily seen from outside. The process for packaging the double-packaged easily oxidizable article of the present invention does not need any complicated procedure nor any special apparatus, and requires a small number of process steps. In the following comparison Table 1 shows the change of the oxygen permeability before and after the heat sterilization; Table 2 shows the oxidation deterioration of tryptophan solution before and after the heat sterilization and during the storing test; Table 3 shows the absorbancy of a substance eluted into the packed liquid drug after the heat sterilization. In the double-packaged easily oxidizable article of the present invention, a vessel filled with the easily oxidizable article is packaged with a flexible packaging bag having an inorganic oxide layer, which has little humidity and temperature dependency, and high oxygen barrier properties, wherein the oxygen barrier properties change little before and after the heat sterilization processing, thus the heat sterilization can be done while the vessel is packaged in the flexible packaging bag, and the oxidation and deterioration of the easily oxidizable article during heat sterilization can be prevented. Since the high oxygen barrier properties can be maintained even after the heat sterilization, the flexible packaging bag has high inhibitory power on oxidation and deterioration of the easily oxidizable article during the subsequent storing period. Accordingly, it is not necessary to wrap the vessel filled with the easily oxidizable article again with a new bag having high oxygen barrier properties, after the heat sterilization. The vessel filled with the easily oxidizable article does not allow its components to migrate into the contents, and highly prevents the permeation of components excluding a gas from outside. The migration of the bag material components into the contents, which is seen when the easily oxidizable article is directly filled in a bag having high oxygen barrier properties and subjected to the heat sterilization treatment, can be substantially prevented, to assure high safety of the contents for use. In addition to that, the double-packaged easily oxidizable article can be made to have transparency, the mixing of a foreign substance into the content can be easily observed to allow easy quality control, and high safety of the contents is assured from this point of view as well. The process of packaging the double-packaged easily. oxidizable article of the present invention does not require any complicated process nor special apparatus, and has small number of steps, i.e. it is a simple process and particularly when a series of steps are carried out continuously, the production amount can be increased to lower the cost. The product can be supplied to hospitals as it is or after packed in a box. Brief Explanation of Drawings Fig. 1 illustrates a sectional view of a flexible packaging bag according to one embodiment of the present invention, wherein the upper side of the figure shows the inside of the flexible packaging bag, and the lower side of the figure shows the outside of the flexible packaging bag. Fig.2 illustrates a plan view of a doubly packaged easily oxidizable article of the present invention. [Explanation of Reference Numbers] 1. Plastic layer having heat-sealing characteristics 2. Inorganic oxide layer 3. Plastic layer 4. Adhesive layer 5. Plastic layer 6. Adhesive layer 21. Flexible packaging bag 22. Vessel 23. Easily oxidizable article. Oxygen permeability before and after the heat sterilization before after before after Example 1 0.5 0.8 Reference Example 1 580 591 Example 2 0.5 0.7 Reference Example 2 586 556 Example 3 0.5 0.8 Reference Example 3 2.7 6.0 Example 4 0.5 0.6 Reference Example 4 2.7 34.5 Example 5 0.5 0.6 Reference Example 5 0.4 25.4 Example 6 0.9 1.2 Reference Example 6 4.2 20.3 Change in transmissivity of 0.4 w% Trp aqueous solution at 430 nm Storing period Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 before retort 99.6 99.6 99.6 99.6 99.7 99.7 after retort 98.6 97.7 98.2 98.5 98.0 98.3 44°C, 1 month 89.7 80.0 85.4 80.5 84.0 78.2 44°C, 3 months. 44.6 44.1 46.8 43.0 44.9 40.2 44°C, 6 months 19.3 16.1 20.5 20.0 20.2 15.2 Storing period Reference Example 1 Reference Example 2 Reference Example 3 Reference Example 4 Reference Example 5 Reference Example 6 before retort 98.8 99.1 98.8 99.2 99 99.1 after retort 96.7 96.5 97.6 97.7 96.9 97.5 44°C, 1 month 51.2 62.6 72.3 68.2 70.5 74.2 44 °C, 3 months 4.5 3.8 14.7 4.7 12.3 15 44°C, 6 months 0.0 0.1 9.1 0.2 3.3 4.6 Absorbancy 210 nm 220 nm 240 nm Example 7 0.085 0.053 0.022 Example 8 0.062 0.040 0.018 Example 9 0.049 0.032 0.016 Example 10 0.093 0.056 0.026 Example 11 0.088 0.054 0.022 Reference Example 7 0.006 0.005 0.003 Reference Example 8 0.006 0.005 0.004 Reference Example 9 0.398 0.217 0.081 Reference Example 10 0.312 0.171 0.064 Reference Example 11 0.349 0.191 0.071

Claims: An easily oxidizable article in a double-package, comprising a flexible packaging bag in which one or more hermetically sealed plastic vessels filled with an easily oxidizable article, are packaged and hermetically sealed; wherein the flexible packaging bag comprises a plastic layer having heat-sealing characteristics, an inorganic oxide layer and a plastic layer laminated in the stated order from the inside to the outside of the bag. An easily oxidizable article according to claim 1, wherein the inorganic oxide layer is a silicon oxide layer and/or an aluminum oxide layer. An easily oxidizable article according to claim 1 or claim 2, which has been subjected to heat sterilization. A process for packaging an easily oxidizable article in a double-package, comprising a flexible packaging bag in which one or more hermetically sealed plastic vessels filled with an easily oxidizable article, are packaged and hermetically sealed, wherein the easily oxidizable article is charged into the plastic vessel, the vessel is hermetically sealed and packaged in a flexible packaging bag comprising a plastic layer having heat-sealing characteristics, an inorganic oxide layer and a plastic layer which are laminated in the stated order from the inside to the outside of the bag, by vacuum packaging or by filling under an inert gas, then heat sterilization treatment is carried out in hot, water or in steam.

Inventors: ITO SACHIYO, MATSUMOTO SHINICHI, MATSUO NORISHIGE, ITO, SACHIYO, MATSUMOTO, SHINICHI, MATSUO, NORISHIGE, Ito, Sachiyo, c/o Technology &amp; Eng. Lab., Matsumoto, Shinichi, c/o Technology &amp; Eng. Lab., Matsuo, Norishige, c/o Technology &amp; Eng. Lab.
Applicants: AJINOMOTO KK, AJINOMOTO CO., INC.
Application year: 1994
Main classification: B32B27
IPC codes: A61J1, B65D30, B32B27, A61L2, B65D77, B65D65, B65D81